Ophthalmic Implant for Delivering Therapeutic Substances

ABSTRACT

Described are implantable therapeutic devices, systems and methods to treat a patient. The device includes a hollow refillable housing for implantation within the posterior segment of an eye through a penetration in the sclera including a proximal retention structure protruding outward from a proximal end region of the housing, an access portion opening, and a penetrable barrier positioned at least in part within the access portion opening, the penetrable barrier configured to be repeatedly penetrated. A rigid porous structure is positioned within a region of the housing away from the access portion opening into a reservoir chamber extends along an axis between the penetrable barrier and the porous structure includes a volume sized to deliver therapeutic amounts of a therapeutic agent to the eye for an extended period of time. A cover is coupled to at least an upper surface of the proximal retention structure.

CROSS-REFERENCE TO PRIORITY DOCUMENT

This application claims the benefit of priority of U.S. ProvisionalPatent Application Ser. No. 61/806,267, entitled “Ophthalmic Implant forDelivering Therapeutic Substances,” filed Mar. 28, 2013. Priority of thefiling date is hereby claimed and the disclosure of the provisionalpatent application is hereby incorporated by reference in its entirety.

BACKGROUND

Diseases that affect vision can be treated with a variety of therapeuticagents, but the delivery of drugs to the eye continues to bechallenging. Injections of therapeutic via the eye can be painful,involve some risk of infection, hemorrhage and retinal detachment.Depending on the frequency, intra-ocular injections can betime-consuming for both patient and physician. Consequently, in at leastsome instances the drug may be administered less often than theprescribed frequency resulting in sub-optimal treatment benefit.Further, bolus intra-ocular injections may not provide the idealpharmacokinetics and pharmacodynamics. A bolus injection of drug intothe vitreous humor of a patient can result in a peak drug concentrationseveral times higher than the desired therapeutic amount and then beforethe patient is able to get the next injection drop to a drugconcentration that is far below therapeutic effectiveness.

SUMMARY

In one aspect, disclosed is an implantable therapeutic device to treat apatient. The device includes a hollow refillable housing forimplantation within the posterior segment of an eye through apenetration in the sclera of the eye. The housing has a proximal endregion. A proximal retention structure protrudes outward from theproximal end region and has an access portion opening. A penetrablebarrier is positioned at least in part within the access portion openingand is configured to be repeatedly penetrated. A rigid porous structureis positioned within a region of the housing away from the accessportion opening. A reservoir chamber extends along an axis between thepenetrable barrier and the porous structure. The reservoir chamberincludes a volume sized to deliver therapeutic amounts of a therapeuticagent to the eye for an extended period of time. The access portionopening opens into the reservoir chamber. A cover is coupled to at leastan upper surface of the proximal retention structure.

In some variations, one or more of the following can optionally beincluded in any feasible combination in the above methods, apparatus,devices, and systems.

The access portion opening can be over-molded by the cover. The covercan encapsulate and bond the proximal retention structure and an uppersurface of the penetrable barrier can be positioned within the accessportion opening. The cover can encapsulate and bond to at least an uppersurface of the proximal retention structure. The cover can encapsulateand bond to a lower surface of the proximal retention structure. Thecover can maintain a seal of the reservoir chamber volume. The cover andthe proximal retention structure can have the same shape profile. Thecover and the penetrable barrier can be penetrated during filling of thereservoir chamber. The cover and the penetrable barrier can beconfigured to reseal after penetration of the reservoir chamber. Theproximal retention structure can include one or more through-holes. Thepenetrable barrier can be pre-molded and the cover can be over-molded.The penetrable barrier can be a soft, high strength material and thecover can be a high durometer material. The cover can be a translucentmaterial. The device can further include an anchor positioned within theaccess portion opening and in contact with at least a portion of thepenetrable barrier. The penetrable barrier can further include a distalregion that is flared and positioned within a proximal end region of thereservoir chamber.

In an interrelated aspect, disclosed is an implantable therapeuticdevice to treat a patient having a hollow refillable housing forimplantation within the posterior segment of an eye through apenetration in the sclera of the eye. The housing has a proximal endregion. A proximal retention structure is protruding outward from theproximal end region and includes an access portion opening. A penetrablebarrier is positioned at least in part within the access portionopening. The penetrable barrier is configured to be repeatedlypenetrated. A rigid porous structure is positioned within a region ofthe housing away from the access portion opening. A reservoir chamberextends along an axis between the penetrable barrier and the porousstructure. The reservoir chamber has a volume sized to delivertherapeutic amounts of a therapeutic agent to the eye for an extendedperiod of time. The access portion opening opens into the reservoirchamber. An anchor is positioned within the access portion opening andin contact with at least a portion of the penetrable barrier.

In some variations, one or more of the following can optionally beincluded in any feasible combination in the above methods, apparatus,devices, and systems.

The penetrable barrier can be pre-molded with soft, high strengthmaterial. The anchor can be formed of a high durometer material thatresists deformation. The penetrable barrier can be bonded to the anchorcreating a single septum structure. The anchor can engage an undercutfeature in the proximal end of housing. The penetrable barrier can applyradial compression to the anchor. The device can further include a covercovering an upper surface of the proximal retention structure. Thedevice can further include a sealing element positioned within aproximal end region of the reservoir chamber and coupled to thepenetrable barrier.

More details of the devices, systems and methods are set forth in theaccompanying drawings and the description below. Other features andadvantages will be apparent from the description and drawings

BRIEF DESCRIPTION OF THE DRAWINGS

These and other aspects will now be described in detail with referenceto the following drawings. Generally speaking the figures are not toscale in absolute terms or comparatively but are intended to beillustrative. Also, relative placement of features and elements may bemodified for the purpose of illustrative clarity.

FIG. 1 is a cross-sectional, schematic view of a portion of the humaneye;

FIG. 2 is a cross-sectional, schematic view of a portion of the humaneye having an implementation of a therapeutic device implanted therein;

FIG. 3A is an exploded, perspective view of an implementation of atherapeutic device;

FIGS. 3B-3C are exploded, side views of the therapeutic device of FIG.3A;

FIGS. 3D-3E are top and bottom views, respectively, of the therapeuticdevice of FIG. 3A;

FIG. 3F is a side, cross-sectional view of the therapeutic device ofFIG. 3A;

FIGS. 4A-4B are perspective and cross-sectional partial views,respectively, of an implementation of a therapeutic device;

FIG. 5 is a side, cross-sectional partial view of an implementation of atherapeutic device;

FIG. 6. is a side, cross-sectional partial view of an implementation ofa therapeutic device.

DETAILED DESCRIPTION

Described herein are implantable devices, systems and methods of use forthe delivery of one or more therapeutics for the treatment of diseases.The devices and systems described herein can deliver therapeutics toselect regions and structures of the body over a variety of periods oftime.

The devices and systems described herein have improved penetrable accessportions for the repeated injection and long-term treatment andimplantation of the device. It should be appreciated that the penetrableaccess portions as described herein can be used with a number of variousdifferent implantable therapeutic devices including one or more of thosedevices described U.S. Pat. No. 8,399,006; U.S. Pat. No. 8,623,395; PCTPat. Publication No. WO2012/019136; PCT Pat. Publication No.WO2012/019047; and PCT Pat. Publication No. WO 2012/065006; the entiredisclosures of which are incorporated herein by reference thereto.

Eye Anatomy

FIG. 1 is a cross-sectional, schematic view of a portion of the humaneye showing the anterior chamber, posterior chamber and vitreous body ofthe eye. The eye 10 is generally spherical and is covered on the outsideby the sclera 24. The retina 26 lines the inside posterior segment ofthe eye 10 and includes the macula 32. The retina 26 registers the lightand sends signals to the brain via the optic nerve. The bulk of the eye10 is filled and supported by the vitreous body (vitreous humor) 30, aclear, jelly-like substance disposed between the lens 22 and the retina26. The elastic lens 22 is located near the front of the eye 10. Thelens 22 provides adjustment of focus and is suspended within a capsularbag from the ciliary body 20, which contains the muscles that change thefocal length of the lens 22. A volume in front of the lens 22 is dividedinto two by the iris 18, which controls the aperture of the lens 22 andthe amount of light striking the retina 26. The pupil is a hole in thecenter of the iris 18 through which light entering anteriorly passes.The volume between the iris 18 and the lens 22 is the posterior chamber.The volume between the iris 18 and the cornea 12 is the anteriorchamber. Both chambers are filled with a clear liquid known as aqueoushumor.

The cornea 12 extends to and connects with the sclera 24 at a locationcalled the limbus 14 of the eye. The conjunctiva 16 of the eye isdisposed over the sclera 24 and the Tenon's capsule (not shown) extendsbetween the conjunctiva 16 and the sclera 24. The eye 10 also includes avascular tissue layer called the choroid 28 that is disposed between aportion of the sclera 24 and the retina 26. The ciliary body 20 iscontinuous with the base of the iris 18 and is divided anatomically intopars plica and pars plana, a posterior flat area approximately 4 mmlong. The pars plana region 25 is an example of a region of the eyesuitable for placement and retention of the devices described herein.The eye 10 can include an insertion of the tendon of the superior rectusmuscle to couple the sclera 24 of the eye to the superior rectus muscle.The devices described herein can be positioned in many locations of thepars plana region 25, for example away from tendon of the superiorrectus muscle and one or more of posterior to the tendon, anterior tothe tendon, under the tendon, or with nasal or temporal placement of thetherapeutic device.

FIG. 2 shows an implementation of the therapeutic device 100 implantedat the pars plana region 25. The device 100 can be positioned so as toextend from the pars plana region 25 through the sclera 24 into theposterior segment of the eye including the vitreous body 30 so as torelease the therapeutic agent into the vitreous body 30. The therapeuticdevice 100 can include a proximal, retention structure 120, such as asmooth protrusion at a proximal end region of the device 100, configuredfor placement along the sclera 24. In some implementations, theretention structure 120 can be positioned under the conjunctiva 16 suchthat the conjunctiva 16 can cover the therapeutic device and protect thetherapeutic device 100. When the therapeutic agent is inserted orinjected into the device 100, the conjunctiva 16 may be lifted away,incised, or punctured with a needle to access the therapeutic device100.

It should be appreciated that the devices and systems described hereincan be positioned in many locations of the eye and need not be implantedspecifically as shown in the figures or as described herein. The devicesand systems described herein can be used to deliver therapeutic agent(s)for an extended period of time to one or more of the following tissues:intraocular, intravascular, intraarticular, intrathecal, pericardial,intraluminal and intraperitoneal. Although specific reference is madebelow to the delivery of treatments to the eye, it also should beappreciated that medical conditions besides ocular conditions can betreated with the devices and systems described herein. For example, thedevices and systems can deliver treatments for inflammation, infection,and cancerous growths. Any number of drug combinations can be deliveredusing any of the devices and systems described herein.

It should be appreciated that the devices and systems described hereincan incorporate any of a variety of features described herein and thatelements or features of one implementation of a device and systemdescribed herein can be incorporated alternatively or in combinationwith elements or features of another implementation of a device andsystem described herein as well as the various implants and featuresdescribed in U.S. Pat. No. 8,399,006; U.S. Pat. No. 8,623,395; PCT Pat.Publication No. WO2012/019136; PCT Pat. Publication No. WO2012/019047;and PCT Pat. Publication No. WO 2012/065006. For example, the septumfeatures described herein may be used with any of the variousimplementations of a device or system. For the sake of brevity, explicitdescriptions of each of those combinations may be omitted although thevarious combinations are to be considered herein. Additionally,described herein are different methods for implantation and access ofthe devices. The various implants can be implanted, filled, refilledetc. according to a variety of different methods and using a variety ofdifferent devices and systems. Provided are some representativedescriptions of how the various devices may be implanted and accessed,however, for the sake of brevity explicit descriptions of each methodwith respect to each implant or system may be omitted.

Implants

In a first implementation and as shown in FIGS. 3A-3F, the device 100can include a housing 130, a penetrable barrier 140 and a porousstructure 150. The housing 130 can be a rigid, hollow refillable housingfor implantation within an interior chamber of the eye, such as theposterior segment of an eye through a penetration in the sclera of theeye. The housing 130 can have a proximal end region and a distal endregion. The housing 130 can have an inner surface that defines, at leastin part, a reservoir chamber 160 for holding a therapeutic material oragent(s) (see FIG. 3F). The penetrable barrier 140 can be positionedwithin a proximal end region of the housing 130 such as within anopening 180 in an access portion of the device that leads into areservoir chamber 160 of the device. The porous structure 150 can bepositioned within another region of the housing 130 a distance away fromthe penetrable barrier 140 such as within an opening 152 leading out ofthe reservoir chamber 160 of the device. For example, the porousstructure 150 can be positioned near a distal end region of the housing130 opposite the location of the more proximal penetrable barrier 140.The reservoir chamber 160 can have a volume sized to deliver therapeuticamounts of therapeutic agent to the eye for an extended period of timeand the porous structure 150 can be configured to release therapeuticagent contained within the reservoir chamber 160 over the extendedperiod of time. The housing 130 can include a retention structure 120that can protrude outward from the proximal end region of the housing130. The access portion opening 180 can be an opening in the device 100that extends into the reservoir chamber 160. The penetrable barrier 140can be positioned, at least in part, within the access portion opening180 such that it forms a seal with the proximal end region of thehousing 130. As will be described in more detail below, the devicesdescribed herein can also include a cover 110 coupled to at least aregion of the device such as the retention structure 120. The cover 110can cover, coat, cap, encapsulate, bond or otherwise couple to at leastthe penetrable barrier 140 of the device. The cover 110 can beconfigured to improve the integrity of the penetrable barrier 140 andits sealing engagement within the access portion opening 180 forrepeated injection and long-term implantation.

Again with respect to FIGS. 3A-3F and as mentioned above, a distal endregion of the housing 130 can include another opening 152, for exampleopposite the proximal access portion opening 180 into the reservoirchamber 160, that extends between the inside of the reservoir chamber160 out of the housing 130. The porous structure 150 can be coupled toor positioned, at least in part, within the opening 152. It should beappreciated that the porous structure 150 can be coupled to orpositioned within other regions besides the distal end region of thehousing 130. The porous structure 150 can be affixed within an opening152 in distal end of housing 130, for example with glue or othermaterial(s). Alternatively or in combination, the distal end of thehousing 130 can include an inner diameter sized to receive the porousstructure 150, and the housing 130 can include a stop to position theporous structure 150 at a predetermined location on the distal end so asto define a predetermined size of reservoir chamber 160.

Still with respect to FIGS. 3A-3F, the reservoir chamber 160 within thehousing 130 of the device 100 can extend along axis 100A between thepenetrable barrier 140 positioned proximally within the access portionopening 180 to the location of the porous structure 150. Therapeuticformulations injected into device 100 can be released from the reservoirchamber 160 in accordance with the volume of the reservoir chamber 160and a release characteristic or release rate index of the porousstructure 150. The volume of the reservoir chamber 160 can be sized todeliver therapeutic amounts of a therapeutic agent to the eye for anextended period of time. The volume of the reservoir chamber 160 can besubstantially determined by an inner cross sectional area of the housing130, such as the distance between the proximal, penetrable barrier 140and the porous structure 150. The release rate index (RRI) can be usedto determine the release of the therapeutic from the device 100. RRIencompasses (PA/FL) where P comprises the porosity, A comprises aneffective area, F comprises a curve fit parameter corresponding to aneffective length and L comprises a length or thickness of the porousstructure 150. Additional details regarding release characteristics ofthe porous structure 150 that can be used in the various devicesdescribed herein can be found, for example, in PCT Publication No. WO2012/065006, which is incorporated herein by reference in its entirety.

The housing 130 can have a dimension such that its length generallyexceeds its width or diameter. The housing 130 can have a diameter sizedwithin a range, for example, from at least about 0.5 mm to at leastabout 4 mm, from at least about 1 mm to at least about 3 mm. In someimplementations the diameter of the housing 130 at its widest point canbe about 2 mm, for example. The housing 130 can have a length sized soas to extend from the conjunctiva 16 to the vitreous body 30 along axis100A to release the therapeutic agent into the vitreous body 30. Thehousing 130 can have a length sized within a range, for example, from atleast about 2 mm to at least about 14 mm, from at least about 4 mm to atleast about 10 mm. In some implementations, the length of the housing130 can be about 7 mm, for example. The above dimensions are provided asexample dimensions and are not intended to be limiting. It should beappreciated that a variety and combination of dimensions are to beconsidered herein.

The housing 130 and reservoir chamber 160 can each (although notnecessarily both) have an elliptical or oval cross-sectional shape, forexample. This elongation of the device along one direction can allow forincreased drug in the reservoir chamber 160 with a decrease interferencein vision, for example, as the major axis of the ellipse can be alignedsubstantially with the circumference of the pars plana region 25 of theeye extending substantially around the cornea 12 of the eye, and theminor axis of the ellipse can be aligned radially with the eye so as todecrease interference with vision as the short axis of the ellipseextends toward the optical axis of the eye corresponding to thepatient's line of sight through the pupil. Although reference is made toan elliptical or oval cross-section, many cross-sectional sizes andshapes can be used such as circular, square or rectangular with a shortdimension extending toward the pupil of the eye and the long dimensionextending along the pars plana of the eye.

One or more regions of the housing 130 of the devices described hereincan be formed of a substantially rigid, biocompatible material. In someimplementations, the walls of the housing 130 including at least theproximal retention structure 120 down to and including the porousstructure 150 are substantially rigid such that the reservoir chamber160 has a substantially constant volume when the therapeutic agent isreleased from the device so as to maintain a stable release rateprofile, for example when the patient moves. The reservoir chamber 160can remain substantially rigid and have a substantially constant volumeeven during injection of the therapeutic agent into the device, forexample a device already implanted in the eye.

One or more regions of the housing 130, one or more regions of theretention structure 120 as well as other portions of the devicesdescribed herein, alone or in combination, can be formed of one or moreof many biocompatible materials including, but not limited to materialssuch as acrylates, polymethylmethacrylate, siloxanes, metals, titaniumstainless steel, polycarbonate, polyetheretherketone (PEEK),polyethylene, polyethylene terephthalate (PET), polyimide,polyamide-imide, polypropylene, polysulfone, polyurethane,polyvinylidene fluoride, polyphenylene polyphenylsulfone or PTFE, andothers. Alternatively or in combination, one or more portions of thedevices described herein, such as the housing 130, can be formed atleast in part from an optically transmissive material such that thehousing 130 can be translucent or transparent, such that when the device100 is loaded with therapeutic agent the reservoir chamber 160 can bevisualized outside the patient prior to implantation, for example wheninjected with a formulation of therapeutic agent prior to implantationin the physician's office. This visualization of the reservoir chamber160 can be helpful to ensure that the reservoir chamber 160 is properlyfilled with therapeutic agent by the treating physician or assistantprior to implantation. For example, transparency can enablevisualization, for example, using an indirect ophthalmoscope, of thecontents of the reservoir chamber 160 of an implanted device allowingone to confirm that no air is trapped in the device and/or verify theclarity of the device contents. A cloudy appearance, for example, mayindicate that some degree of contamination, microbial or otherwise, hasoccurred. The biocompatible, optically transmissive materials caninclude one or more of acrylate, polyacrylate, methlymethacraylate,polymethlymethacrylate (PMMA), polyacarbonate, glass or siloxane.

The porous structure 150 can include one or more of a release controlelement, a release control mechanism, permeable membrane, asemi-permeable membrane, a material having at least one hole disposedtherein, channels formed in a rigid material, straight channels,nano-channels, nano-channels etched in a rigid material, laser drilledholes, laser etched nano-channels, a capillary channel, a plurality ofcapillary channels, one or more tortuous channels, sintered material,sintered rigid material, sintered glass, sintered ceramic, sinteredmetal, sintered titanium, tortuous micro-channels, sinterednano-particles, an open cell foam or a hydrogel such as an open cellhydrogel. Porous structures considered herein are described in U.S. Pat.No. 8,399,006; U.S. Pat. No. 8,623,395; PCT Publication No.WO2012/019136; PCT Publication No. WO2012/019047; and PCT PublicationNo. WO 2012/065006; the entire disclosures of which are incorporatedherein by reference thereto.

Again with respect to FIGS. 3A-3F and as mentioned above, the retentionstructure 120 can protrude outward from the proximal end region of thehousing 130. At least a first surface of the retention structure 120 canbe configured to contact the sclera 24 and, in some implementations, canbe configured to contact the conjunctiva 16 on at least a second surfaceof the retention structure 120. For example, at least a portion of theunderside of the retention structure 120 can contact the sclera 24 andat least a portion of the upper side of the retention structure 120 cancontact the conjunctiva 16. In some implementations, the retentionstructure 120 can be configured to contact the sclera 24 such that theretention structure 120 is at least partially embedded within thethickness of the sclera 24 and does not necessarily sit on an uppersurface of the sclera or the conjunctiva.

The retention structure 120 can include a narrowed portion 121 and awider, flanged portion 122 extending proximally from the narrowedportion 121. The narrowed portion 121 can have a cross-section sized tofit in an elongate incision or a puncture through the pars plana region25 without causing gaping of the tissue near either end of the incision.For example, an incision can be made with a device having a straight,flat blade, for example a 3.2 mm blade. Penetrating the sclera with sucha blade can result in exposed scleral tissue that may need to be sealed(e.g. 6.4 mm or 2×3.2 mm). A cross-sectional region of an implantpositioned within the cut region of the sclera, for example having aperimeter of 6.4 mm and a diameter of about 2 mm, could open the woundsuch that there would be relatively large voids on either side of thedevice, for example about 2.2 mm between either side of the device andthe farthest aspects of the exposed sclera. These voids can result incut portions of the sclera remaining exposed and unsealed. The geometryof the narrowed portion 121 of the devices described herein can bedesigned to minimize the length of cut scleral tissue that remainsexposed and/or unsealed.

The narrowed portion 121 can have a first cross-sectional distanceacross, or first dimensional width, and a second cross-sectionaldistance across, or second dimensional width, in which the firstcross-sectional distance across is greater than the secondcross-sectional distance across providing the narrowed portion 121 withan elongate cross-sectional profile. The elongate cross section of thenarrowed portion 121 can be sized in many ways to fit the incision. Theelongate cross section can have a first dimension longer than a seconddimension and can have one or more of many shapes such as dilated slit,dilated slot, lentoid, oval, ovoid, or elliptical. It should also beappreciated that the narrowed portion 121 can have other cross sectionalshapes, for example, a circular shape, if desired. The dilated slitshape and dilated slot shape can correspond to the shape assumed by thescleral tissue when cut and dilated. The lentoid shape can correspond toa biconvex lens shape. The elongate cross-section of the narrowedportion 121 can include a first curve along a first axis and a secondcurve along a second axis that is different than the first curve. Thenarrowed portion 121 can be sized and configured to receive the sclera24 upon implantation in the eye 10 when the flanged portion 122 ispositioned between the sclera 24 and the conjunctiva 16 and the distalend of the housing 130 extends into the vitreous body 30.

Flanged portion 122 of the retention structure 120 can include a firstdistance across and a second distance across. The first distance acrosscan be greater than the second distance across (see FIGS. 3B and 3C, forexample). The first distance across can result in the flanged portion122 having a diameter greater than a largest diameter of the housing 130(see e.g., FIG. 3B) whereas the second distance across can result in theflanged portion 122 having a diameter equal to or less than a largestdiameter of the housing 130 (see e.g., FIG. 3C). The flanged portion 122can have a variety of shapes, such as rectangular, square, oval,elliptical, circular, teardrop, polygonal or other shape. The flangedportion 122 can be formed as a smooth protrusion configured forplacement along a portion of the sclera 24. In some implementations, theflanged portion 122 is positioned under the conjunctiva 16, such thatthe conjunctiva 16 covers and protects the device 100. The flangedportion 122 can be formed from a translucent material such that thephysician can visualize tissue under the flanged portion 122 to assessthe patient and to decrease appearance of the device 100 when implanted.

As mentioned above, the penetrable barrier 140 can be positioned, atleast in part, within access portion opening 180 sealing the reservoirchamber 160 on a proximal end region of the device 100. The penetrablebarrier 140 can be a septum configured to receive and be repeatedlypenetrated by a sharp object such as a needle for injection of thetherapeutic agent into the reservoir chamber 160. The penetrable barrier140 can be configured to re-seal when the sharp object is removed. Thepenetrable barrier 140 can be a pre-molded soft, high strength material.In some implementations, the penetrable barrier 140 can be formed fromone or more elastic materials such as siloxane, rubber, or anotherliquid injection molding silicone elastomer such as NUSIL MED-4810(NuSil Silicone Technology, Carpinteria, Calif.). In someimplementations, the penetrable barrier 140 can include an opaquematerial and/or a colored material such that it can be visualized by thetreating physician.

Repeated injection as well as long-term implantation of the device 100can affect the integrity of the penetrable barrier 140. For example,repeated injection through the penetrable barrier 140 can at leastpartially damage the device and negatively affect the seal between theinner surfaces of the housing 130, retention structure 120 and the outersurfaces of the penetrable barrier 140. Further, over time afterimplantation the penetrable barrier 140 can loosen relative to thehousing 130. Described herein are features to improve the integrity ofthe penetrable barrier 140, its sealing engagement with the accessportion opening 180 of the housing 130 and/or retention structure 120,and the effectiveness of the access region for repeated injection andlong-term implantation of the re-fillable devices described herein.

As described above and as best shown in FIGS. 3A-3F, the penetrablebarrier 140 can be positioned within a proximal end region of thehousing 130 at least in part within an opening of the access portion180. As such, the overall shape of the external surface of thepenetrable barrier 140 can correspond generally to the shape of thesurface(s) near the access portion opening 180 against which thepenetrable barrier 140 contacts to mate and seal. It should beappreciated that the points of contact between the penetrable barrier140 and the housing 130 can vary. The penetrable barrier 140 can makecontact, for example sealing contact, with at least one or more surfacesor regions of the upper end of the reservoir chamber, the housing 130,the retention structure 120, the narrowed portion 121, the flangedportion 122, the access portion opening 180, and/or a combinationthereof.

As best shown in FIGS. 3B-3C, the penetrable barrier 140 can have anupper region 144, a middle region 141, and a distal region 142. Theupper region 144 can be sized to reside within and mate with at least aportion of the flanged portion 122. The upper region 144 can form anupper surface of the penetrable barrier 140 available through the accessregion opening 180 of the device. In some implementations, the outersurface of the upper region 144 can be beveled to correspond with theshape of and provide optimum mating engagement with an inner surface ofthe retention structure 120 that can also be beveled (see FIG. 3F).Engagement between the upper region 144 and the access portion opening180 aids in forming a seal and retaining the penetrable barrier 140within the access portion opening 180. The middle region 141 can besized to reside within and mate with an inner surface of the narrowedportion 121 of the retention structure 120. As such, the middle region141 can be a reduced diameter region or form a “waist” in the penetrablebarrier 140. Alternatively, the middle region 141 can be relativelyannular and have a generally planar outer surface configured to contacta corresponding planar surface forming the opening of the access region180.

In some implementations, the distal region 142 can have a diameter thatis the same as or greater than the narrowed portion 121 of the retentionstructure 120 such that the distal region 142 helps to preventwithdrawal of the penetrable barrier 140 out of the access region 180.For example, the distal region 142 can have one or more tabs, a flaredskirt, flange, rib or other feature of enlarged diameter compared to themiddle and/or upper regions 141, 144 and sized to reside within and matewith at least a portion of the retention structure 120 located distal tothe narrowed portion 121 and/or an upper region of the reservoir chamber160 such as with an inner wall of the housing 130. In someimplementations, the flange can have an upper surface configured tocontact an inner wall surface near the upper end of the reservoirchamber 160 that surrounds the opening 180 of the access portion. Thefeatures of the distal region 142 having an enlarged diameter comparedto the middle or upper regions 144, 141, such as the one or more tabscan also aid in forming a seal and retaining the penetrable barrier 140within the access portion opening 180. For example, as best shown inFIG. 3C, the distal region 142 of the penetrable barrier 140 can includea first tab 142 a positioned on a first region of the penetrable barrier140 and a second tab 142 b positioned on a second region of thepenetrable barrier 140, such as a side opposite or a distance away fromthe first region. The tabs 142 a, 142 b can project away from thelongitudinal axis 100A providing a cross-sectional diameter of thepenetrable barrier 140 in at least one direction that is greater thatthe cross-sectional diameter of the middle region 141. Thecross-sectional diameter of the penetrable barrier 140 distal to themiddle region 141 in at least a first direction can be equal to, more orless than the cross-sectional diameter of the upper region 144. Itshould be appreciated that the distal region 142 can have one, two,three, four, or more tabs spaced around the wall of the penetrablebarrier 140. It should also be appreciated that the entire distal region142 of the penetrable barrier 140 can be flared away from thelongitudinal axis 100A of the penetrable barrier 140 as shown in FIG. 4Bto better engage an upper region of the housing 130 near the accessregion 180. In further implementations, the distal region 142 of thepenetrable barrier 140 can be include a flange of an enlarged diameter.It should be appreciated that the distal region 142 as well as theentire penetrable barrier 140 itself can have a variety of shapes andfeatures that act to improve retention within the upper end of thereservoir chamber 160. The features of one implementation of thepenetrable barrier 140 can be used in combination or in the alternativewith one or more implementations of the devices described herein.

The penetrable barrier 140 can be adhered within the device 100, forexample, in at least a portion of the access portion opening 180 of theretention structure 120. Alternatively, the penetrable barrier 140 canbe positioned into a proximal region of the device 100 in anadhesion-free manner and rely on the mating features between theexternal surface of the penetrable barrier 140 with the correspondingsurfaces of the access portion opening 180 against which the penetrablebarrier 140 abuts and seals.

As mentioned above, the devices described herein can be coupled to acover 110 that can be configured to improve the integrity of thepenetrable barrier 140 and its sealing engagement with the accessportion opening 180 for repeated injection and long-term implantation.This provides a benefit to a device intended to be implanted long-termand re-filled while implanted, such as those described herein. The cover110 can cap, coat, bond, encapsulate, cover, or otherwise couple to oneor more components of the devices described herein. For example, atleast a portion of a proximal end region of the device 100, includingone or more combinations of the upper surface of the penetrable barrier140 positioned within the opening of the access portion 180, an uppersurface of the proximal retention structure 120 including the flangedportion 122, a lower surface of the proximal retention structure 120including the flanged portion 122, the narrowed portion 121 of theretention structure 120, and at least a portion of an outer surface ofthe housing 130 near the proximal end region.

FIGS. 4A-4B show an implementation of a device in which the accessportion opening 180, the penetrable barrier 140 and the retentionstructure 120 can be over-molded by the cover 110 such that the cover110 can encapsulate and bond the access portion opening 180 and theupper surface of the penetrable barrier 140 positioned within the accessportion opening 180. The cover 110 can encapsulate and bond to at leastan upper surface of the proximal retention structure 120 as well as thelower surface of the proximal retention structure 120 (see, for example,FIG. 4B). The cover 110 can also encapsulate the flanged portion 122such that the cover 110 bonds to at least the upper surface and also thelower surface of the flanged portion 122. The penetrable barrier 140 canbe exposed or accessible on a proximal end region. The cover 110 canextend across the entire proximal end region of the device 100 such thatit bonds to the flanged portion 122 and to the proximal end region ofthe penetrable barrier 140 positioned therein. As such, the cover 110can supplement the bond between the penetrable barrier 140 and the innersurfaces of the device near the access portion opening 180 such aswithin the flanged region 120 and the inner surfaces of the proximal endregion of the housing 130. The cover 110 can maintain or help tomaintain a seal of the reservoir chamber volume. In someimplementations, the cover 110 maintains the seal of the penetrablebarrier 140 within the access portion opening 180 such that the seal ofthe reservoir chamber 160 need not rely on bonding between the surfacesof the housing 130 and the surfaces of the penetrable barrier 140. Insome implementations, the cover 110 eliminates any need for a bondbetween the housing 130 and the penetrable barrier 140. Certain surfacetreatments can also be used during manufacturing of the devicesdescribed herein to enhance bonding between various components,including for example but not limited to, bonding primer agents such asNUSIL MED 161 or other surface activation techniques such as plasmatreatment of the surfaces to be bonded.

The cover 110 and the proximal retention structure 120 (or any otherregion coupled to the cover 110 such as the flanged portion 122), canhave corresponding shape profiles. The thickness of the over-moldedcover 110 can vary from approximately 0.007″ to approximately 0.025″.The cover 110 can extend beyond the outer diameter of the flangedportion 122 as best shown in FIGS. 4A and 4B. The cover 110 can alsoextend upward from the upper surface of the flanged portion 122 andprovide a slightly thicker and slightly higher profile to the accessportion under the conjunctiva. During injection of the therapeutic agentinto the reservoir chamber 160, the needle can extend through the cover110 as it penetrates the barrier 140. The cover 110, like the penetrablebarrier 140, can be configured to re-seal when the needle or other sharpobject is withdrawn.

The proximal retention structure 120 can include one or morethrough-holes, apertures, indentations or other features. Again withrespect to FIGS. 4A-4B, the flanged portion 122 can include one or moreapertures 125 extending therethrough. Upon application of the cover 110,the apertures 125 can create mechanical struts of the over-molded covermaterial that extend through one or more regions of the flanged portion122. The mechanical struts of over-molded cover material can providesome anchoring support as well as facilitating good filling of theover-mold. The apertures 125 can also allow for a thin, uniform layer ofover-mold material to form on the underside of the flanged portion 122or other another region of the retention structure during over-molding.It should be appreciated, however, that mechanical struts of theover-molded material can be formed by over-molded material extendingonly partially through apertures in the flanged portion 122. Further,instead of apertures 125, the flanged portion 122 can include onlypartial-thickness holes or indentations in the flanged portion 122. Theindentations can be on an external surface of the flanged portion 122such as in the upper and/or lower surfaces of the flanged portion 122.The external surfaces of the flanged portion 122 can also be texturedsuch that the over-molded material of the cover 110 can penetrate andfill additional indented regions of the flanged portion 122 to provide abetter coupling between the flanged portion 122 and the material of thecover 110.

The cover 110 can be an over-molded, high durometer material such as atranslucent, liquid silicone rubber like MED-4880 or MED-4860 (NuSilSilicone Technology, Carpinteria, Calif.). The penetrable barrier 140positioned within the proximal end region of the housing 130 can be apre-molded soft, high strength material such as a liquid injectionmolding silicone elastomer such as MED-4810 (NuSil Silicone Technology,Carpinteria, Calif.).

FIG. 5 illustrates another implementation of a device that can include,alternatively or in combination with the cover 110, an anchor 250 tosecure the septum structure within the access portion of the housing130. The anchor 250 can provide further support to the penetrablebarrier 140 as well as providing perimeter seal and added physicalintegrity useful during repeated penetration of the barrier 140 torefill the device. In some implementations, the anchor 250 can be anannular element encircling at least a portion of the penetrable barrier140. An inner surface of the anchor 250 can contact and encircle atleast a portion of the outer surface of the penetrable barrier 140. Insome implementations, the anchor 250 encircles the upper region 144, themiddle region 141, the distal region 142 or a combination of one or moreof the upper, middle and distal regions of the penetrable barrier 140.The upper region 144 of the penetrable barrier 140 can be beveled suchthat the outer diameter of the upper region 144 is larger than the outerdiameter of the middle region 141 of the penetrable barrier 140.Similarly, the shape of the inner surface of the anchor 250 can bebeveled to match the shape of the outer surface of the penetrablebarrier 140. Similarly, the inner surface of the anchor 250 can beshaped to match the outer surface of the distal region 142 of thepenetrable barrier 140, which can be straight or flared or have one ormore tabs or flanged regions as described above. Further, the outersurface of the anchor 250 can have a geometry that matches at least aportion of the geometry of the housing 130 at the access portion. Forexample, the outer surface of the 250 can engage with an undercutfeature 252 in the proximal end of the housing 130. It should beappreciated that the anchor 250 can be, but is not necessarily, annularor ring-shaped. The anchor 250 can be any of a variety of shapes and caninclude one or more features that can be bonded to at least a region ofthe penetrable barrier. The outer surface of the anchor 250 can have anyof a variety of shapes, including, but not limited to the rounded shapeas shown in FIG. 5, curvilinear such as oval, circular, or elliptical,as well as being angular in shape such as triangular, rectangular, orother number of angles. The anchor 250 can have sufficient physicalrobustness so as to translate to a secure mechanical interference withinternal aspects of the rigid, body device in the area of the penetrablebarrier.

The penetrable barrier 140 can be pre-molded with a soft, high strengthmaterial such as a liquid injection molding silicone elastomer such asMED-4810 (NuSil Silicone Technology, Carpinteria, Calif.). The anchor250 can be formed of a higher durometer material such as a translucent,liquid silicone rubber like MED-4880 (NuSil Silicone Technology,Carpinteria, Calif.). The pre-mold penetrable barrier 140 can be bondedto the annular anchor 250 creating a single septum structure forinsertion within the proximal end of the housing 130. The pre-moldpenetrable barrier 140 and anchor 250 can be bonded together within thehousing 130 or can be bounded outside the device and loaded intopositioned once a single septum structure is formed. The higherdurometer of the anchor 250 can resist deformation and create amechanical lock fixing the location of the septum in the housing 130.The pre-mold penetrable barrier 140 can apply radial compression to theouter anchor 250 and housing 130 to maintain septum seal performance.The radial compression of the penetrable barrier 140 can encouragere-sealing after penetration following filling or re-filling of thereservoir chamber, for example re-sealing of a needle track upon removalof the needle. The radial compression of the penetrable barrier 140 canbe provided by the pre-mold penetrable barrier 140 being larger indimension relative to the access portion of the housing 130 in which itis positioned and the access portion of the housing 130 being formed ofa more rigid material than the softer, pre-mold penetrable barrier 140.

FIG. 6 illustrates an interrelated implementation of a device that caninclude, alternatively or in combination with the cover 110, an anchor250. As described above, the anchor 250 can secure the septum structurewithin the access portion opening 180 of the housing 130. The anchor 250can provide further support to the penetrable barrier 140 as well asproviding perimeter seal and added physical integrity. As with otherimplementations described herein, the anchor 250 can be an annularelement encircling at least a portion of the penetrable barrier 140. Aninner surface of the anchor 250 can contact and encircle at least aportion of the outer surface of the penetrable barrier 140. The innersurface of the anchor 250 can have a shape that corresponds to the outersurface of the penetrable barrier 140 and the outer surface of theanchor 250 can have a shape that corresponds to the inner surface of theaccess portion opening 180 of the housing 130, for example such that itengages an undercut feature 252 in the proximal end of the housing 130.The anchor 250 can be formed of a high durometer material to providefurther support to the penetrable barrier 140 as well as providingperimeter seal and added physical integrity as described above. Thepenetrable barrier 140 can be a pre-molded, low durometer material alsoas described above. Further, the penetrable barrier 140 can be oversizedsuch that the penetrable barrier 140 provides radial compression to theanchor 250 to provide improved needle track sealing as described above.

As described above, the penetrable barrier 140 can include a distalregion 142 having a flared, flanged or otherwise enlarged diametercompared to the middle region 141 and/or upper region 144 of thepenetrable barrier 140. The enlarged distal region 142 can be positionedwithin the access portion opening 180, for example, where the accessportion opening 180 opens into the reservoir chamber 160 at a proximalend region of the reservoir chamber 160. As shown in FIG. 6, thepenetrable barrier 140 can also include a sealing element 254 near itsdistal end region that is flared and/or creates a “skirt” within aproximal end region of the reservoir chamber 160. The sealing element254 can be positioned in a proximal end of the reservoir chamber 160 ofthe housing 130 to provide a secondary seal and to prevent withdrawal ofthe penetrable barrier 140 in a proximal direction. It should beappreciated the sealing element 254 can be a separate element coupled tothe penetrable barrier 140, for example to the distal region 142 of thepenetrable barrier 140. Alternatively, the sealing element 254 can beintegral with the penetrable barrier 140 such as the flared distal endregion 142 shown in FIG. 4B. As such, the sealing element 254 can be alow durometer material that is the same as or different from thematerial of the penetrable barrier 140. It should also be appreciatedthat the variations described above, such as the cover 110 can also beincorporated with the implementation shown in FIG. 6. It should beappreciated that the one or more of the components described herein canoptionally be included in any feasible combination with the variousimplementations described herein.

The housing 130 can be machined from a piece of material, or injectionmolded, so as to form the retention structure 120, flange 122 and/or thenarrowed portion 121. As described above, the penetrable barrier 140 canbe pre-molded and the cover 110 can be over-molded. Alternatively, thecover 110 can be pre-molded and bonded to the pre-molded penetrablebarrier 140. The penetrable barrier 140 and cover 110 can be the samematerial and over-molded around the flange 122 using a single stepinjection molding process. Alternatively, the penetrable barrier 140 orcover 110 can be two different materials and over molded around theflange and cured in two independent steps. Further, the anchor 250and/or sealing element 254 can be pre-molded and bonded to pre-moldedpenetrable barrier 140. The anchor 250 and/or sealing element 254 can becasted in the housing and the pre-penetrable barrier 140 can becompressed into the housing and bonded to the anchor 250 and/or sealingelement 254. Alternatively, the sealing element 254 can be formed by adistal flared portion of the pre-molded penetrable barrier 140.

Therapeutics

Initial filling of the device 100 with one or more therapeutic agentscan occur prior to insertion or after insertion in a patient's eye. Thepenetrable barrier 140 as well as the cover 110, if present, can bepenetrated with a needle or access device attached to a syringe orinjection device containing therapeutic agent. The cover 110 and thepenetrable barrier 140 can be penetrated during filling and/or refillingof the reservoir chamber 160. The needle or access device can beinserted through the penetrable barrier 140 until a distal opening ofthe needle enters the reservoir chamber 160. The contents of the syringeor injection device can be injected into the reservoir chamber 160 andthe needle or access device can be removed from the penetrable barrier140. The cover 110 and the penetrable barrier 140 can be configured toreseal after penetration during filling and/or refilling of thereservoir chamber 160. The penetrable barrier 140 can reseal around thepath created by the needle or access device upon its removal. The device100 also can be periodically refilled with therapeutic agent followingsurgical placement as needed by accessing the implanted device 100 andwithout necessitating device removal. The conjunctiva 16 can be liftedor incised away. Alternatively, the conjunctiva can be pierced with theneedle or access device used to fill the device 100 such that a singlepenetration is performed through each of the conjunctiva, cover 110 (ifpresent), and penetrable barrier 140. Once the needle or access deviceis inserted and located at the appropriate depth within the reservoirchamber 160, injection of fresh therapeutic solution or exchange ofpre-existing reservoir contents with fresh therapeutic solution can takeplace.

The therapeutic devices described herein can be implanted in the eye totreat the eye for as long as is helpful and beneficial to the patient.For example the device can be implanted for at least about 1 year, 2years, 3 years, 4 year, 5 years and up to permanently for the life ofthe patient. Alternatively or in combination, the device can be removedwhen no longer helpful or beneficial for treatment of the patient. Inother implementations, the device can be implanted for at least about 4years to 10 years, for example a duration of treatment period for achronic disease such as diabetic macular edema or age-related maculardegeneration. The device can be periodically refilled in the physician'soffice with new therapeutic agent as indicated by disease progression.For diseases such as age-related macular degeneration, the device can berefilled as frequently as once every week, bi-weekly, monthly,bi-monthly, every 3 months, every 4 to 6 months, every 3 to 9 months,every 12 months, or any other period as indicated to treat a disease.

It should be appreciated that a variety of diseases and/or conditionscan be treated with the devices and systems described herein, forexample: glaucoma, macular degeneration, retinal disease, proliferativevitreoretinopathy, diabetic retinopathy, uveitis, keratitis,cytomegalovirus retinitis, cystoid macular edema, herpes simplex viraland adenoviral infections and other eye diseases, eye infections(including, but not limited to, infections of the skin, eyelids,conjunctivae, and/or lacrimal excretory system), orbital cellulitis,dacryoadenitis, hordeolum, blepharitis, conjunctivitis, keratitis,corneal infiltrates, ulcers, endophthalmitis, panophthalmitis, viralkeratitis, fungal keratitis herpes zoster ophthalmicus, viralconjunctivitis, viral retinitis, uveitis, strabismus, retinal necrosis,retinal disease, vitreoretinopathy, diabetic retinopathy,cytomegalovirus retinitis, cystoids macular edema, herpes simplex viraland adenoviral injections, scleritis, mucormycosis, canaliculitis,acanthamoeba keratitis, toxoplasmosis, giardiasis, leishmanisis,malaria, helminth infection, etc. It also should be appreciated thatmedical conditions besides ocular conditions can be treated with thedevices and systems described herein. For example, the devices candeliver drugs for the treatment of inflammation, infection, cancerousgrowth. It should also be appreciated that any number of drugcombinations can be delivered using any of the devices and systemsdescribed herein.

The devices described herein can be used to deliver essentially anysubstance. As used herein, “substance,” “drug” or “therapeutic” is anagent or agents that ameliorate the symptoms of a disease or disorder orameliorate the disease or disorder including, for example, smallmolecule drugs, proteins, nucleic acids, polysaccharides, and biologicsor combination thereof. Therapeutic agent, therapeutic compound,therapeutic regimen, or chemotherapeutic include conventional drugs anddrug therapies, including vaccines, which are known to those skilled inthe art. Therapeutic agents include, but are not limited to, moietiesthat inhibit cell growth or promote cell death, that can be activated toinhibit cell growth or promote cell death, or that activate anotheragent to inhibit cell growth or promote cell death. Optionally, thetherapeutic agent can exhibit or manifest additional properties, suchas, properties that permit its use as an imaging agent, as describedelsewhere herein. Exemplary therapeutic agents include, for example,cytokines, growth factors, proteins, peptides or peptidomimetics,bioactive agents, photosensitizing agents, radionuclides, toxins,anti-metabolites, signaling modulators, anti-cancer antibiotics,anti-cancer antibodies, angiogenesis inhibitors, radiation therapy,chemotherapeutic compounds or a combination thereof. The drug may be anyagent capable of providing a therapeutic benefit. In an embodiment, thedrug is a known drug, or drug combination, effective for treatingdiseases and disorders of the eye. In non-limiting, exemplaryembodiments, the drug is an antiinfective agent (e.g., an antibiotic orantifungal agent), an anesthetic agent, an anti-VEGF agent, ananti-inflammatory agent, a biological agent (such as RNA), anintraocular pressure reducing agent (i.e., a glaucoma drug), or acombination thereof. Non-limiting examples of drugs are provided below.

The therapeutic agent can include a macromolecule, for example anantibody or antibody fragment. The therapeutic macromolecule can includea VEGF inhibitor, for example commercially available Lucentis™. The VEGF(Vascular Endothelial Growth Factor) inhibitor can cause regression ofthe abnormal blood vessels and improvement of vision when released intothe vitreous humor of the eye. Examples of VEGF inhibitors includeLucentis™ Avastin™, Macugen™ and VEGF Trap. The therapeutic agent caninclude small molecules such as of a corticosteroid and analoguesthereof. For example, the therapeutic corticosteroid can include one ormore of trimacinalone, trimacinalone acetonide, dexamethasone,dexamethasone acetate, fluocinolone, fluocinolone acetate, or analoguesthereof. Alternatively or in combination, the small molecules oftherapeutic agent can include a tyrosine kinase inhibitor comprising oneor more of axitinib, bosutinib, cediranib, dasatinib, erlotinib,gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib,sunitinib, toceranib, vandetanib, or vatalanib, for example. Thetherapeutic agent can include an anti-VEGF therapeutic agent. Anti-VEGFtherapies and agents can be used in the treatment of certain cancers andin age-related macular degeneration. Examples of anti-VEGF therapeuticagents suitable for use in accordance with the embodiments describedherein include one or more of monoclonal antibodies such as bevacizumab(Avastin™) or antibody derivatives such as ranibizumab (Lucentis™), orsmall molecules that inhibit the tyrosine kinases stimulated by VEGFsuch as lapatinib (Tykerb™), sunitinib (Sutent™), sorafenib (Nexavar™)axitinib, or pazopanib. The therapeutic agent can include a therapeuticagent suitable for treatment of dry AMD such as one or more ofSirolimus™ (Rapamycin), Copaxone™ (Glatiramer Acetate), Othera™Complement C5aR blocker, Ciliary Neurotrophic Factor, Fenretinide orRheopheresis. The therapeutic agent can include a therapeutic agentsuitable for treatment of wet AMD such as one or more of REDDI4NP(Quark), Sirolimus™ (Rapamycin), ATG003; Regeneron™ (VEGF Trap) orcomplement inhibitor (POT-4). The therapeutic agent can include a kinaseinhibitor such as one or more of bevacizumab (monoclonal antibody), BIBW2992 (small molecule targeting EGFR/Erb2), cetuximab (monoclonalantibody), imatinib (small molecule), trastuzumab (monoclonal antibody),gefitinib (small molecule), ranibizumab (monoclonal antibody),pegaptanib (small molecule), sorafenib (small molecule), dasatinib(small molecule), sunitinib (small molecule), erlotinib (smallmolecule), nilotinib (small molecule), lapatinib (small molecule),panitumumab (monoclonal antibody), vandetanib (small molecule) or E7080(targeting VEGFR2NEGFR2, small molecule commercially available fromEsai, Co.)

A variety of therapeutic agents can be delivered using the drug deliveryimplants described herein, including: anesthetics, analgesics, celltransport/mobility impending agents such as colchicine, vincristine,cytochalasin B and related compounds; antiglaucoma drugs includingbeta-blockers such as timolol, betaxolol, atenolol, and prostaglandins,lipid-receptor agonists or prostaglandin analogues such as bimatoprost,travoprost, latanoprost, unoprostone etc; alpha-adrenergic agonists,brimonidine or dipivefrine, carbonic anhydrase inhibitors such asacetazolamide, methazolamide, dichlorphenamide, diamox; andneuroprotectants such as nimodipine and related compounds.

Additional examples include antibiotics such as tetracycline,chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,oxytetracycline, chloramphenicol, gentamycin, and erythromycin;antibacterials such as sulfonamides, sulfacetamide, sulfamethizole andsulfisoxazole; anti-fungal agents such as fluconazole, nitrofurazone,amphotericin B, ketoconazole, and related compounds; anti-viral agentssuch as trifluorothymidine, acyclovir, ganciclovir, DDI, AZT, foscamet,vidarabine, trifluorouridine, idoxuridine, ribavirin, proteaseinhibitors and anti-cytomegalovirus agents; antiallergenics such asmethapyriline; chlorpheniramine, pyrilamine and prophenpyridamine;anti-inflammatories such as hydrocortisone, dexamethasone, fluocinolone,prednisone, prednisolone, methylprednisolone, fluorometholone,betamethasone and triamcinolone; decongestants such as phenylephrine,naphazoline, and tetrahydrazoline; miotics, muscarinics andanti-cholinesterases such as pilocarpine, carbachol, di-isopropylfluorophosphate, phospholine iodine, and demecarium bromide; mydriaticssuch as atropine sulfate, cyclopentolate, homatropine, scopolamine,tropicamide, eucatropine; sympathomimetics such as epinephrine andvasoconstrictors and vasodilators; Ranibizumab, Bevacizamab, andTriamcinolone.

Antiinflammatories, such as non-steroidal anti-inflammatories (NSAIDs)may also be delivered, such as cyclooxygenase-1 (COX-1) inhibitors(e.g., acetylsalicylic acid, for example ASPIRIN from Bayer AG,Leverkusen, Germany; ibuprofen, for example ADVIL from Wyeth,Collegeville, Pa.; indomethacin; mefenamic acid), COX-2 inhibitors(CELEBREX from Pharmacia Corp., Peapack, N.J.; COX-1 inhibitors),including a prodrug NEPAFENAC; immunosuppressive agents, for exampleSirolimus (RAPAMUNE, from Wyeth, Collegeville, Pa.), or matrixmetalloproteinase (MMP) inhibitors (e.g., tetracycline and tetracyclinederivatives) that act early within the pathways of an inflammatoryresponse. Anticlotting agents such as heparin, antifibrinogen,fibrinolysin, anti clotting activase, etc., can also be delivered.

Antidiabetic agents that may be delivered using the disclosed implantsinclude acetohexamide, chlorpropamide, glipizide, glyburide, tolazamide,tolbutamide, insulin, aldose reductase inhibitors, etc. Some examples ofanti-cancer agents include 5-fluorouracil, adriamycin, asparaginase,azacitidine, azathioprine, bleomycin, busulfan, carboplatin, carmustine,chlorambucil, cisplatin, cyclophosphamide, cyclosporine, cytarabine,dacarbazine, dactinomycin, daunorubicin, doxorubicin, estramustine,etoposide, etretinate, filgrastin, floxuridine, fludarabine,fluorouracil, fluoxymesterone, flutamide, goserelin, hydroxyurea,ifosfamide, leuprolide, levamisole, lomustine, nitrogen mustard,melphalan, mercaptopurine, methotrexate, mitomycin, mitotane,pentostatin, pipobroman, plicamycin, procarbazine, sargramostin,streptozocin, tamoxifen, taxol, teniposide, thioguanine, uracil mustard,vinblastine, vincristine and vindesine.

Hormones, peptides, steroids, nucleic acids, saccharides, lipids,glycolipids, glycoproteins, and other macromolecules can be deliveredusing the present implants. Examples include: endocrine hormones such aspituitary, insulin, insulin-related growth factor, thyroid, growthhormones; heat shock proteins; immunological response modifiers such asmuramyl dipeptide, cyclosporins, interferons (including α, β, and γinterferons), interleukin-2, cytokines, FK506 (anepoxy-pyrido-oxaazcyclotricosine-tetrone, also known as Tacrolimus),tumor necrosis factor, pentostatin, thymopentin, transforming factorbeta2, erythropoetin; antineogenesis proteins (e.g., anti-VEGF,Interferons), among others and anticlotting agents includinganticlotting activase. Further examples of macromolecules that can bedelivered include monoclonal antibodies, brain nerve growth factor(BNGF), ciliary nerve growth factor (CNGF), vascular endothelial growthfactor (VEGF), and monoclonal antibodies directed against such growthfactors. Additional examples of immunomodulators include tumor necrosisfactor inhibitors such as thalidomide.

In addition, nucleic acids can also be delivered wherein the nucleicacid may be expressed to produce a protein that may have a variety ofpharmacological, physiological or immunological activities. Thus, theabove list of drugs is not meant to be exhaustive. A wide variety ofdrugs or agents may be used in the present invention, withoutrestriction on molecular weight, etc.

Other agents include anti-coagulant, an anti-proliferative, imidazoleantiproliferative agent, a quinoxaline, a phsophonylmethoxyalkylnucleotide analog, a potassium channel blocker, and/or a syntheticoligonucleotide,5-[1-hydroxy-2-[2-(2-methoxyphenoxyl)ethylamino]ethyl]-2-methylbenzenesulfonamide,a guanylate cyclase inhibitor, such as methylene blue, butylatedhydroxyanisole, and/or N-methylhydroxylamine, 2-(4-methylaminobutoxy)diphenylmethane, apraclonidine, a cloprostenol analog or a fluprostenolanalog, a crosslinked carboxy-containing polymer, a sugar, and water, anon-corneotoxic serine-threonine kinase inhibitor, a nonsteroidalglucocorticoid antagonist, miotics (e.g., pilocarpine, carbachol, andacetylcholinesterase inhibitors), sympathomimetics (e.g., epinephrineand dipivalylepinephxine), beta-blockers (e.g., betaxolol, levobunololand timolol), carbonic anhydrase inhibitors (e.g., acetazolamide,methazolamide and ethoxzolamide), and prostaglandins (e.g., metabolitederivatives of arachidonic acid, or any combination thereof.

Additional examples of beneficial drugs that may be employed and thespecific conditions to be treated or prevented are disclosed inRemington, supra; The Pharmacological Basis of Therapeutics, by Goodmanand Gilman, 19th edition, published by the MacMillan Company, London;and The Merck Index, 13th Edition, 1998, published by Merck & Co.,Rahway, N.J., which is incorporated herein by reference.

While this specification contains many specifics, these should not beconstrued as limitations on the scope of what is claimed or of what maybe claimed, but rather as descriptions of features specific toparticular embodiments. Certain features that are described in thisspecification in the context of separate embodiments can also beimplemented in combination in a single embodiment. Conversely, variousfeatures that are described in the context of a single embodiment canalso be implemented in multiple embodiments separately or in anysuitable sub-combination. Moreover, although features may be describedabove as acting in certain combinations and even initially claimed assuch, one or more features from a claimed combination can in some casesbe excised from the combination, and the claimed combination may bedirected to a sub-combination or a variation of a sub-combination.Similarly, while operations are depicted in the drawings in a particularorder, this should not be understood as requiring that such operationsbe performed in the particular order shown or in sequential order, orthat all illustrated operations be performed, to achieve desirableresults. Only a few examples and implementations are disclosed.Variations, modifications and enhancements to the described examples andimplementations and other implementations may be made based on what isdisclosed.

In the descriptions above and in the claims, phrases such as “at leastone of” or “one or more of” may occur followed by a conjunctive list ofelements or features. The term “and/or” may also occur in a list of twoor more elements or features. Unless otherwise implicitly or explicitlycontradicted by the context in which it is used, such a phrase isintended to mean any of the listed elements or features individually orany of the recited elements or features in combination with any of theother recited elements or features. For example, the phrases “at leastone of A and B;” “one or more of A and B;” and “A and/or B” are eachintended to mean “A alone, B alone, or A and B together.” A similarinterpretation is also intended for lists including three or more items.For example, the phrases “at least one of A, B, and C;” “one or more ofA, B, and C;” and “A, B, and/or C” are each intended to mean “A alone, Balone, C alone, A and B together, A and C together, B and C together, orA and B and C together.”

Use of the term “based on,” above and in the claims is intended to mean,“based at least in part on,” such that an unrecited feature or elementis also permissible.

What is claimed is:
 1. An implantable therapeutic device to treat apatient, comprising: a hollow refillable housing for implantation withinthe posterior segment of an eye through a penetration in the sclera ofthe eye, the housing having a proximal end region; a proximal retentionstructure protruding outward from the proximal end region and comprisingan access portion opening; a penetrable barrier positioned at least inpart within the access portion opening, the penetrable barrierconfigured to be repeatedly penetrated; a rigid porous structurepositioned within a region of the housing away from the access portionopening; a reservoir chamber extending along an axis between thepenetrable barrier and the porous structure, the reservoir chambercomprising a volume sized to deliver therapeutic amounts of atherapeutic agent to the eye for an extended period of time, wherein theaccess portion opening opens into the reservoir chamber; and a covercoupled to at least an upper surface of the proximal retentionstructure.
 2. The device of claim 1, wherein the access portion openingis over-molded by the cover.
 3. The device of claim 2, wherein the coverencapsulates and bonds the proximal retention structure and an uppersurface of the penetrable barrier positioned within the access portionopening.
 4. The device of claim 2, wherein the cover encapsulates andbonds to at least an upper surface of the proximal retention structure.5. The device of claim 4, wherein the cover encapsulates and bonds to alower surface of the proximal retention structure.
 6. The device ofclaim 1, wherein the cover maintains a seal of the reservoir chambervolume.
 7. The device of claim 1, wherein the cover and the proximalretention structure have the same shape profile.
 8. The device of claim1, wherein the cover and the penetrable barrier are penetrated duringfilling of the reservoir chamber.
 9. The device of claim 8, wherein thecover and the penetrable barrier are configured to reseal afterpenetration of the reservoir chamber.
 10. The device of claim 1, whereinthe proximal retention structure includes one or more through-holes. 11.The device of claim 1, wherein the penetrable barrier is pre-molded andthe cover is over-molded.
 12. The device of claim 1, wherein thepenetrable barrier is a soft, high strength material and the cover is ahigh durometer material.
 13. The device of claim 1, wherein the cover isa translucent material.
 14. The device of claim 1, further comprising ananchor positioned within the access portion opening and in contact withat least a portion of the penetrable barrier.
 15. The device of claim 1,wherein the penetrable barrier further comprises a distal region that isflared and positioned within a proximal end region of the reservoirchamber.
 16. An implantable therapeutic device to treat a patient,comprising: a hollow refillable housing for implantation within theposterior segment of an eye through a penetration in the sclera of theeye, the housing having a proximal end region; a proximal retentionstructure protruding outward from the proximal end region and comprisingan access portion opening; a penetrable barrier positioned at least inpart within the access portion opening, the penetrable barrierconfigured to be repeatedly penetrated; a rigid porous structurepositioned within a region of the housing away from the access portionopening; a reservoir chamber extending along an axis between thepenetrable barrier and the porous structure, the reservoir chambercomprising a volume sized to deliver therapeutic amounts of atherapeutic agent to the eye for an extended period of time, wherein theaccess portion opening opens into the reservoir chamber; and an anchorpositioned within the access portion opening and in contact with atleast a portion of the penetrable barrier.
 17. The device of claim 16,wherein the penetrable barrier is pre-molded with soft, high strengthmaterial.
 18. The device of claim 16, wherein the anchor is formed of ahigh durometer material that resists deformation.
 19. The device ofclaim 16, wherein the penetrable barrier is bonded to the anchorcreating a single septum structure.
 20. The device of claim 16, whereinthe anchor engages an undercut feature in the proximal end of housing.21. The device of claim 16, wherein the penetrable barrier appliesradial compression to the anchor.
 22. The device of claim 16, furthercomprising a cover covering an upper surface of the proximal retentionstructure.
 23. The device of claim 16, further comprising a sealingelement positioned within a proximal end region of the reservoir chamberand coupled to the penetrable barrier.